Wang Xiaomeng, Geng Shijia, Dai Lina, Niu Yan, Chen Jie, Dong Chongyang, Liu Rujin, Shi Yuanjia, Zhang Jing, Zhao Ningxia, Gao Zhanfeng, Gao Shang, Yang Xi
Graduate School of Inner Mongolia Medical University, Inner Mongolia Medical University, Hohhot 010110, PR China; College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China.
College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, PR China; Medical Experiments Center, Inner Mongolia Medical University, Hohhot 010110, PR China.
Life Sci. 2025 Jan 15;361:123334. doi: 10.1016/j.lfs.2024.123334. Epub 2024 Dec 23.
Atherosclerosis involves the buildup of macrophage-derived foam cells in the arterial intima. Facilitating the egress of these cells from plaques can significantly slow disease progression. The transmembrane receptor Unc5b, a vascular-specific axon guidance receptor, is upregulated in foam cells, and inhibits their migration from the plaques. However, the mechanisms underlying Unc5b's regulation of foam cell production and retention within plaques, along with its downstream signaling pathways, remain insufficiently understood.
We employed both a foam cell model and an ApoE-deficient mouse model of atherosclerosis to evaluate these effects. Western blotting, RT-PCR, wound healing assays, and immunofluorescence staining were performed to explore the role of Unc5b in foam cell migration.
Unc5b played a role in advancing atherosclerosis by regulating the P53-cuproptosis pathway, thereby inhibiting the migration of foam cells. Stimulation of Raw264.7 cells with oxidized low-density lipoprotein (ox-LDL) resulted in increased cuproptosis and inflammation, impacting migration regulation. Macrophage-derived foam cell migration was prevented by Unc5b via the P53-cuproptosis signaling pathway. Notably, PFT-α (a P53 inhibitor) and VI (a Cu chelator) counteracted the inhibitory effect of ox-LDL on migration. Similarly, upregulation of cuproptosis-related proteins was observed within the aortic sinus plaques of ApoE mice fed a hyperlipidemic diet. Importantly, the progression of atherosclerosis induced by a hyperlipidemic diet can be effectively reversed by PFT-α and VI.
These findings underscore Unc5b's role in promoting inflammation, inhibiting macrophage migration, and promoting atherosclerotic development via the P53-cuproptosis signaling pathway.
动脉粥样硬化涉及巨噬细胞源性泡沫细胞在动脉内膜的积聚。促进这些细胞从斑块中流出可显著减缓疾病进展。跨膜受体Unc5b是一种血管特异性轴突导向受体，在泡沫细胞中上调，并抑制其从斑块中迁移。然而，Unc5b调节泡沫细胞产生和在斑块内滞留的机制及其下游信号通路仍未得到充分了解。
我们采用泡沫细胞模型和动脉粥样硬化的载脂蛋白E缺陷小鼠模型来评估这些作用。进行蛋白质免疫印迹、逆转录聚合酶链反应、伤口愈合试验和免疫荧光染色，以探讨Unc5b在泡沫细胞迁移中的作用。
Unc5b通过调节P53-铜死亡途径在动脉粥样硬化进展中发挥作用，从而抑制泡沫细胞迁移。用氧化型低密度脂蛋白（ox-LDL）刺激Raw264.7细胞导致铜死亡和炎症增加，影响迁移调节。Unc5b通过P53-铜死亡信号通路阻止巨噬细胞源性泡沫细胞迁移。值得注意的是，PFT-α（一种P53抑制剂）和VI（一种铜螯合剂）抵消了ox-LDL对迁移的抑制作用。同样，在喂食高脂饮食的载脂蛋白E小鼠的主动脉窦斑块内观察到铜死亡相关蛋白的上调。重要的是，PFT-α和VI可以有效逆转高脂饮食诱导的动脉粥样硬化进展。
这些发现强调了Unc5b在通过P53-铜死亡信号通路促进炎症、抑制巨噬细胞迁移和促进动脉粥样硬化发展中的作用。
